Breast Cancer NCCN Evidence BlocksTM

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NCCN Evidence Blocks TM

Breast Cancer

Version 5.2020 — July 15, 2020

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NCCN Guidelines Version 5.2020 Breast Cancer

NCCN Evidence Blocks

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NCCN Guidelines Index Table of Contents Discussion

*William J. Gradishar, MD/Chair ‡ † Robert H. Lurie Comprehensive Cancer Center of Northwestern University

*Benjamin O. Anderson, MD/Vice-Chair ¶ Fred Hutchinson Cancer Research

Center/Seattle Cancer Care Alliance Jame Abraham, MD ‡ †

Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute Rebecca Aft, MD, PhD ¶

Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine Doreen Agnese, MD ¶

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Kimberly H. Allison, MD ≠ Stanford Cancer Institute Sarah L. Blair, MD ¶

UC San Diego Moores Cancer Center Harold J. Burstein, MD, PhD † Dana-Farber/Brigham and Women’s Cancer Center

Chau Dang, MD †

Memorial Sloan Kettering Cancer Center Anthony D. Elias, MD †

University of Colorado Cancer Center

Sharon H. Giordano, MD, MPH † The University of Texas

MD Anderson Cancer Center Matthew P. Goetz, MD ‡ † Mayo Clinic Cancer Center Lori J. Goldstein, MD † Fox Chase Cancer Center Steven J. Isakoff, MD, PhD † Massachusetts General Hospital Cancer Center

Jairam Krishnamurthy, MD † Fred & Pamela Buffet Cancer Center Janice Lyons, MD §

Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute P. Kelly Marcom, MD †

Duke Cancer Institute Jennifer Matro, MD †

Abramson Cancer Center at the University of Pennsylvania Ingrid A. Mayer, MD †

Vanderbilt-Ingram Cancer Center Meena S. Moran, MD §

Yale Cancer Center/Smilow Cancer Hospital Joanne Mortimer, MD †

City of Hope National Medical Center Ruth M. O'Regan, MD †

University of Wisconsin Carbone Cancer Center

Sameer A. Patel, MD Ÿ Fox Chase Cancer Center Lori J. Pierce, MD § University of Michigan Rogel Cancer Center Hope S. Rugo, MD † UCSF Helen Diller Family Comprehensive Cancer Center Amy Sitapati, MD Þ

UC San Diego Moores Cancer Center Karen Lisa Smith, MD, MPH † The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Mary Lou Smith, JD, MBA ¥ Research Advocacy Network Hatem Soliman, MD † Moffitt Cancer Center

Erica M. Stringer-Reasor, MD † ‡ O'Neal Comprehensive

Cancer Center at UAB Melinda L. Telli, MD † Þ Stanford Cancer Institute John H. Ward, MD ‡ † Huntsman Cancer Institute at the University of Utah Jessica S. Young, MD ¶

Roswell Park Comprehensive Cancer Center

NCCNRashmi Kumar, PhD Jennifer Burns

NCCN Guidelines Panel Disclosures

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^‡Hematology/Hematology oncology

Þ Internal medicine

† Medical oncology

≠ Pathology

¥ Patient advocacy

§ Radiation oncology/

Radiotherapy

Ÿ Reconstructive surgery

¶ Surgery/Surgical oncology

* Discussion Section Writing Committee

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Clinical Trials: NCCN believes that the best management for any patient with cancer is in a clinical trial.

Participation in clinical trials is especially encouraged.

To find clinical trials online at NCCN Member Institutions, click here:

nccn.org/clinical_trials/member_

institutions.aspx.

NCCN Categories of

Evidence and Consensus: All recommendations are category 2A unless otherwise indicated.

See NCCN Categories of Evidence and Consensus.

NCCN Categories of Preference:

All recommendations are considered appropriate.

See NCCN Categories of Preference.

NCCN Breast Cancer Panel Members NCCN Evidence Blocks Definitions (EB-1)

Recommendations for Lobular Carcinoma In Situ were removed from the NCCN Guidelines for Breast Cancer, See NCCN Guidelines for Breast Screening and Diagnosis Noninvasive Breast Cancer:

D uctal Carcinoma In Situ (DCIS) Workup and Primary Treatment (DCIS-1)

DCIS Postsurgical Treatment and Surveillance/Follow-up (DCIS-2) Invasive Breast Cancer:

Clinical Stage, Workup (BINV-1)

Locoregional Treatment of T1–3,N0–1,M0 Disease (BINV-2) Systemic Adjuvant Treatment

• Hormone Receptor-Positive HER2-Positive Disease (BINV-5)

• N ode-Negative Hormone Receptor-Positive HER2-Negative Disease (BINV-6)

• N ode-Positive Hormone Receptor-Positive HER2-Negative Disease (BINV-7)

• Hormone Receptor-Negative HER2-Positive Disease (BINV-8)

• Hormone Receptor-Negative HER2-Negative Disease (BINV-9)

• Favorable Histologies (BINV-10)

Workup Prior to Preoperative Systemic Therapy (BINV-11) A djuvant Systemic Therapy After Preoperative

Systemic Therapy (BINV-15) Surveillance/Follow-Up (BINV-16)

Recurrent/Stage IV (M1) Disease (BINV-17)

Treatment of Local and Regional Recurrence (BINV-18)

Systemic Treatment of Recurrent or Stage IV (M1) Disease (BINV-19) Principles of Biomarker Testing (BINV-A)

Principles of Dedicated Breast MRI Testing (BINV-B)

Fertility and Birth Control (BINV-C) Surgical Axillary Staging (BINV-D) Axillary Lymph Node Staging (BINV-E)

M argin Status Recommendations for DCIS and Invasive Breast Cancer (BINV-F)

Special Considerations to Breast-Conserving Therapy Requiring RT (BINV-G)

P rinciples of Breast Reconstruction Following Surgery (BINV-H)

Principles of Radiation Therapy (BINV-I)

Special Considerations for Breast Cancer in Men (BINV-J) Adjuvant Endocrine Therapy (BINV-K)

Preoperative/Adjuvant Therapy Regimens (BINV-L) Principles of Preoperative Systemic Therapy (BINV-M) G ene Expression Assays for Consideration of Addition of

Adjuvant Systemic Chemotherapy to Adjuvant Endocrine Therapy (BINV-N)

Definition of Menopause (BINV-O)

S ystemic Therapy for ER- and/or PR-Positive Recurrent or Stage IV (M1) Disease (BINV-P)

S ystemic Therapy Regimens for Recurrent or Stage IV (M1) Disease (BINV-Q)

A dditional Targeted Therapies and Associated Biomarker Testing for Recurrent or Stage IV (M1) Disease (BINV-R) Principles of Monitoring Metastatic Disease (BINV-S) Special Considerations:

Phyllodes Tumor (PHYLL-1) Paget’s Disease (PAGET-1)

Breast Cancer During Pregnancy (PREG-1) Inflammatory Breast Cancer (IBC-1) Staging (ST-1)

NCCN Guidelines for Patients^® available at www.nccn.org/patients

The NCCN Guidelines^® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network^® (NCCN^®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Evidence Blocks^TM and NCCN Guidelines are copyrighted by National Comprehensive Cancer Network^®. All rights reserved. The NCCN Evidence Blocks^TM, NCCN Guidelines, and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2020.

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NCCN Guidelines Version 5.2020 Breast Cancer

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NCCN Guidelines Index Table of Contents Discussion NCCN EVIDENCE BLOCKS CATEGORIES AND DEFINITIONS

E = Efficacy of Regimen/Agent S = Safety of Regimen/Agent Q = Quality of Evidence C = Consistency of Evidence A = Affordability of Regimen/Agent Efficacy of Regimen/Agent

5 Highly effective: Cure likely and often provides long-term survival advantage

4 Very effective: Cure unlikely but sometimes provides long-term survival advantage

3 Moderately effective: Modest impact on survival, but often provides control of disease

2 Minimally effective: No, or unknown impact on survival, but sometimes provides control of disease

1 Palliative: Provides symptomatic benefit only

Safety of Regimen/Agent

5 Usually no meaningful toxicity: Uncommon or minimal toxicities; no interference with activities of daily living (ADLs) 4 Occasionally toxic: Rare significant toxicities or low-grade

toxicities only; little interference with ADLs

3 Mildly toxic: Mild toxicity that interferes with ADLs

2 Moderately toxic: Significant toxicities often occur but life threatening/fatal toxicity is uncommon; interference with ADLs is frequent

1 Highly toxic: Significant toxicities or life threatening/fatal toxicity occurs often; interference with ADLs is usual and severe

Note: For significant chronic or long-term toxicities, score decreased by 1

Quality of Evidence

5 High quality: Multiple well-designed randomized trials and/or meta-analyses

4 Good quality: One or more well-designed randomized trials 3 Average quality: Low quality randomized trial(s) or well-designed

non-randomized trial(s)

2 Low quality: Case reports or extensive clinical experience 1 Poor quality: Little or no evidence

Consistency of Evidence

5 Highly consistent: Multiple trials with similar outcomes

4 Mainly consistent: Multiple trials with some variability in outcome 3 May be consistent: Few trials or only trials with few patients,

whether randomized or not, with some variability in outcome 2 Inconsistent: Meaningful differences in direction of outcome

between quality trials

1 Anecdotal evidence only: Evidence in humans based upon anecdotal experience

Affordability of Regimen/Agent (includes drug cost, supportive care, infusions, toxicity monitoring, management of toxicity)

5 Very inexpensive 4 Inexpensive

3 Moderately expensive 2 Expensive

1 Very expensive 54

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1 E S Q C A

Example Evidence Block E = 4 S = 4 Q = 3 C = 4 A = 3 54

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1 E S Q C A

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Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.

All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

DCIS-1

a The panel endorses the College of American Pathologists Protocol for pathology reporting for all invasive and noninvasive carcinomas of the breast. http://www.cap.org.

b For risk criteria, See NCCN Guidelines for Genetic/Familial High-Risk Assessment:

Breast and Ovarian.

c See Principles of Dedicated Breast MRI Testing (BINV-B).

d The use of MRI has not been shown to increase likelihood of negative margins or decrease conversion to mastectomy. Data to support improved long-term outcomes are lacking.

e Re-resection(s) may be performed in an effort to obtain negative margins in patients desiring breast-conserving therapy. Patients in whom adequate surgical margins cannot be achieved with lumpectomy should undergo a total mastectomy. For definition of adequate surgical margins, see Margin Status Recommendations for DCIS and Invasive Breast Cancer (BINV-F).

f Complete axillary lymph node dissection should not be performed in the absence of evidence of invasive cancer or proven axillary metastatic disease in women with apparent pure DCIS. However, a small proportion of patients with apparent pure DCIS will be found to have invasive cancer at the time of their definitive surgical procedure.

Therefore, the performance of a sentinel lymph node procedure should be strongly considered if the patient with apparent pure DCIS is to be treated with mastectomy or with excision in an anatomic location compromising the performance of a future sentinel lymph node procedure.

DIAGNOSIS WORKUP PRIMARY TREATMENT

DCISTis,N0,M0

• History and physical exam

• Diagnostic bilateral mammogram

• Pathology review^a

• Determination of tumor estrogen receptor (ER) status

• Genetic counseling if patient is at risk^b for hereditary breast cancer

• Breast MRI^c,d as indicated

Lumpectomy^e without lymph node surgery^f + whole breast radiation therapy (WBRT) (category 1) with or without boost to tumor bed^g,h,i,j

orTotal mastectomy with or without sentinel node biopsy^f,h + reconstruction (optional)^k

orLumpectomy^ewithout lymph node surgery^f+ accelerated partial breast irradiation (APBI)^g,h,i,j orLumpectomy^ewithout lymph node surgery^f without radiation therapy (RT)^g,h,i,j (category 2B)

See Postsurgical Treatment (DCIS-2)

g See Principles of Radiation Therapy (BINV-I).

h Patients found to have invasive disease at total mastectomy or re-excision should be managed as having clinical stage l or stage ll disease (See ST-1), including lymph node staging.

i See Special Considerations to Breast-Conserving Therapy Requiring Radiation Therapy (BINV-G).

j WBRT following lumpectomy reduces recurrence rates in DCIS by about 50%. Approximately half of the recurrences are invasive and half are DCIS.

A number of factors determine local recurrence risk: palpable mass, larger size, higher grade, close or involved margins, and age <50 years. If the patient and physician view the individual risk as “low,” some patients may be treated by excision alone. Select patients with low-risk DCIS may be considered suitable for APBI if they meet all aspects of the definition of low- risk DCIS from the RTOG 9804 trial, including screen-detected DCIS, low to intermediate nuclear grade, tumor size ≤2.5 cm, and surgical resection with margins negative at >3 mm.

k See Principles of Breast Reconstruction Following Surgery (BINV-H).

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l Available data suggest endocrine therapy provides risk reduction in the ipsilateral breast treated with breast conservation and in the contralateral breast in patients with mastectomy or breast conservation with ER-positive primary tumors. Since a survival advantage has not been demonstrated, individual consideration of risks and benefits is important.

m CYP2D6 genotype testing is not recommended in women who are considering tamoxifen.

Risk reduction therapy for ipsilateral breast following breast- conserving surgery (BCS):

• Consider endocrine therapy for 5 years for:

Patients treated with breast-conserving therapy (lumpectomy) and RT^m (category 1), especially for those with ER-positive DCIS.

The benefit of endocrine therapy for ER-negative DCIS is uncertain Patients treated with excision alone^l

• Endocrine therapy:

Tamoxifen^m for premenopausal patients

Tamoxifen^m or aromatase inhibitor for postmenopausal patients with some advantage for aromatase inhibitor therapy in patients

<60 years or with concerns for thromboembolism Risk reduction therapy for contralateral breast:

• Counseling regarding risk reduction

DCIS POSTSURGICAL TREATMENT SURVEILLANCE/FOLLOW-UP

• Interval history and physical exam every 6–12 mo for 5 y, then annually

• Mammogram every 12 mo (first mammogram 6–12 mo, after breast conservation therapy, category 2B)

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BINV-1

a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.

b Breast MRI may be useful for characterizing axillary and/or internal mammary nodal disease.

See Principles of Dedicated Breast MRI Testing (BINV-B).

c The panel endorses the College of American Pathologists Protocol for pathology reporting for all invasive and noninvasive carcinomas of the breast. http://www.cap.org.

d See Principles of Biomarker Testing (BINV-A).

e For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic.

f See Fertility and Birth Control (BINV-C).

g See NCCN Guidelines for Distress Management.

h Routine systemic staging is not indicated for early breast cancer in the absence of symptoms.

CLINICAL STAGE WORKUP

• History and physical exam

• Imaging:

Diagnostic bilateral mammogram Ultrasound as necessary

Breast MRI^b (optional), with special consideration for mammographically occult tumors

• Pathology review^c

• Determination of tumor estrogen/progesterone receptor (ER/PR) status and HER2 status^d

• Genetic counseling if patient is at risk^e for hereditary breast cancer

• Counseling for fertility concerns if premenopausal

• Pregnancy test in all women of childbearing potential^f(If pregnant, see PREG-1)

• Assess for distress^g

See Locoregional Treatment (BINV-2)

See Workup Prior to Preoperative Systemic Therapy (BINV-11) T0–3,N1,M0

T1–3,N0–1,M0 (If not

considering preoperative systemic therapy)

Recurrent or Stage IV (M1) See Workup for Recurrent or Stage IV (M1) Disease (BINV-17) If considering preoperative systemic therapy for ≥T2 or ≥N1

(Candidates for preoperative systemic therapy, see BINV-M)

i Bone scan or sodium fluoride PET/CT may not be needed if FDG PET/

CT is performed and clearly indicates bone metastasis, on both the PET and CT component.

j FDG PET/CT can be performed at the same time as diagnostic CT. The use of PET or PET/CT is not indicated in the staging of clinical stage I, II, or operable stage III breast cancer. FDG PET/CT is most helpful in situations where standard staging studies are equivocal or suspicious, especially in the setting of locally advanced or metastatic disease.

k FDG PET/CT may also be helpful in identifying unsuspected regional nodal disease and/or distant metastases in locally advanced breast cancer when used in addition to standard staging studies.

Clinical pathologic diagnosis of

inflammatory breast cancer (IBC) See Inflammatory Breast Cancer (IBC-1)

Consider additional studies only if directed by signs or symptoms of metastatic disease:^h

• Complete blood count (CBC)

• Comprehensive metabolic panel, including liver function tests and alkaline phosphatase

• Bone scan indicated if localized bone pain or elevated alkaline phosphatase or sodium fluoride PET/CTⁱ (category 2B)

• Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast indicated if elevated alkaline phosphatase, abnormal liver function tests, abdominal symptoms, or abnormal physical examination of the abdomen or pelvis

• Chest diagnostic CT with contrast (if pulmonary symptoms present)

• FDG PET/CT^j,k (optional)

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NCCN Guidelines Version 5.2020 Invasive Breast Cancer

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l See Surgical Axillary Staging (BINV-D).

m See Axillary Lymph Node Staging (BINV-E) and Margin Status Recommendations for DCIS and Invasive Disease (BINV-F).

n See Special Considerations to Breast-Conserving Therapy Requiring Radiation Therapy (BINV-G).

o Except as outlined in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic and the NCCN Guidelines for Breast Cancer Risk Reduction, prophylactic mastectomy of a breast contralateral to a known unilateral breast cancer is discouraged. When considered, the small benefits from contralateral prophylactic mastectomy for women with unilateral breast cancer must be balanced with the risk of recurrent disease from the known ipsilateral breast cancer, psychological and social issues of bilateral mastectomy, and the risks of contralateral mastectomy. The use of a prophylactic mastectomy contralateral to a breast treated with breast-conserving therapy is very strongly discouraged.

LOCOREGIONAL TREATMENT OF T1–3,N0–1,M0 DISEASE^a

Lumpectomy with surgical axillary staging (category 1)^l,m,n

Total mastectomy with surgical axillary staging^l,m,o (category 1) ± reconstruction^p

≥4 positive^q axillary nodes

1–3 positive axillary nodes

Negative axillary nodes

Whole breast radiation therapy (WBRT) with or without boost^r to tumor bed (category 1), infraclavicular region, supraclavicular area, internal mammary nodes, and any part of the axillary bed at risk (category 1). It is common for RT to follow chemotherapy when chemotherapy is indicated.

WBRT with or without boost^r to tumor bed (category 1). Strongly consider RT to infraclavicular region, supraclavicular area, internal mammary nodes, and any part of the axillary bed at risk.^s It is common for RT to follow chemotherapy when chemotherapy is indicated.

WBRT with or without boost^r to tumor bed, and consider regional nodal irradiation with exclusion of the dissected portion of the axilla in patients with central/medial tumors or tumors >2 cm with other high-risk features (young age or extensive lymphovascular invasion [LVI]).

or Consideration of APBI in selected low-risk patients.^r,t

It is common for RT to follow chemotherapy when chemotherapy is indicated.^u

See Locoregional Treatment (BINV-3)

See BINV-4

p See Principles of Breast Reconstruction Following Surgery (BINV-H).

q Consider imaging for systemic staging, including chest/

abdominal ± pelvic diagnostic CT with contrast, bone scan, and optional FDG PET/CT (See BINV-1).

r See Principles of Radiation Therapy (BINV-I).

s Consider tangents/high tangents for patients who meet ACOSOG Z0011 criteria.

t PBI may be administered prior to chemotherapy.

u Breast irradiation may be omitted in patients ≥70 y of age with ER-positive, clinically node-negative, T1 tumors who receive adjuvant endocrine therapy (category 1).

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BINV-3 Total mastectomy

with surgical axillary staging^l,m (category 1)

± reconstruction^p

≥4 positive axillary nodes^q

1–3 positive axillary nodes^w

Margins positive

Negative axillary nodes and tumor

≤5 cm and negative margins but <1 mm Negative axillary nodes and tumor ≤5 cm and margins ≥1 mm

RT^r to chest wall + infraclavicular region, supraclavicular area, internal mammary nodes, and any part of the axillary bed at risk (category 1). It is common for RT to follow chemotherapy when chemotherapy is indicated.

Strongly consider RT^rto chest wall + infraclavicular region,

supraclavicular area, internal mammary nodes, and any part of the axillary bed at risk. It is common for RT to follow chemotherapy when chemotherapy is indicated.

Re-excision to negative margins is preferred. If not feasible, then strongly consider RT^r to chest wall ± infraclavicular region, ±

supraclavicular area, ± internal mammary nodes and any part of the axillary bed at risk. It is common for RT to follow chemotherapy when chemotherapy is indicated.

Consider RT^r to chest wall,± regional nodal radiation in patients with central/medial tumors or tumors >2 cm with other high-risk features (young age or extensive LVI). It is common for RT to follow chemotherapy when chemotherapy is indicated.

No RT^x

See BINV-4

m See Axillary Lymph Node Staging (BINV-E) and See Margin Status Recommendations for DCIS and Invasive Disease (BINV-F).

q Consider imaging for systemic staging, including chest/abdominal ± pelvic diagnostic CT with contrast, bone scan, and optional FDG PET/CT (See BINV-1).

v See Special Consideration for Breast Cancer in Men (BINV-J).

w In the case of a micrometastasis (>0.2 to ≤2.0 mm), and no axillary dissection, evaluate other patient risk factors when considering RT.

x Postmastectomy RT may be considered for patients with multiple high-risk recurrence factors, including central/medial tumors or tumors >2 cm with other high-risk features such as young age and/or extensive LVI.

Negative axillary nodes and tumor >5 cm

Consider RT^r to chest wall ± infraclavicular region, ± supraclavicular area, ± internal mammary nodes and any part of the axillary

bed at risk. It is common for RT to follow chemotherapy when chemotherapy is indicated.

LOCOREGIONAL TREATMENT OF T1–3,N0–1,M0 DISEASE^a,v

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y According to WHO, carcinoma of no special type (NST) encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.

z There are rare subtypes of metaplastic carcinoma (eg, low-grade adenosquamous and low-grade fibromatosis-like carcinoma) that are

considered to have a favorable prognosis without adjuvant systemic therapies.

aa To be associated with favorable prognosis, the favorable histologic type should be pure (>90% as classified on the surgical excision, not core biopsy alone), not high grade and HER2 negative. If non-typical pathologic or clinical features are present, consider treating as ductal/NST.

HISTOLOGY HORMONE

RECEPTOR STATUS HER2 STATUS^bb SYSTEMIC ADJUVANT TREATMENT

• Ductal/NST^y

• Lobular

• Mixed

• Micropapillary

• Metaplastic^z

Favorable

histologic type:^aa

• Pure tubular

• Pure mucinous

• Pure cribriform

• Encapsulated or solid papillary carcinoma

• Other rare forms^z

ER-positive^bb,cc and/or

PR-positive^bb,cc

ER-negative and PR-negative^bb,cc

ER-positive^ccand/or PR-positive^cc orER-negative and PR-negative

HER2-positive^bb

HER2-negative^bb

HER2-positive^bb

HER2-negative^bb

See Systemic Adjuvant Treatment: Favorable Histologies (BINV-10) See Systemic Adjuvant Treatment: Hormone Receptor Positive - HER2-Positive Disease (BINV-5)

See Systemic Adjuvant Treatment: Node-Negative - Hormone Receptor Positive - HER2-Negative Disease (BINV-6)

See Systemic Adjuvant Treatment: Hormone Receptor Negative - HER2-Positive Disease (BINV-8)

See Systemic Adjuvant Treatment: Hormone Receptor Negative - HER2-Negative Disease (BINV-9)

See Systemic Adjuvant Treatment: Node-Positive - Hormone Receptor Positive - HER2-Negative Disease (BINV-7)

bb Correlation of histology, hormone receptor, and HER2 status should always be done with awareness of unusual/discordant or borderline results. See Principles of of Biomarker Testing (BINV-A).

cc Although patients with cancers with 1%–100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with ER-low–positive (1%–10%) results. The ER-low–

positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers. This should be considered in decision-making for other adjuvant therapy and overall treatment pathway. See Principles of Biomarker Testing (BINV-A).

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BINV-5 SYSTEMIC ADJUVANT TREATMENT: HORMONE RECEPTOR-POSITIVE - HER2-POSITIVE DISEASE^d,v,cc

• Lobular

• Mixed

pT1, pT2, or pT3;

and pN0 or pN1mi (≤2 mm axillary node metastasis)

Node positive (1 or more ipsilateral metastases >2 mm)

Tumor ≤0.5 cm

Tumor 0.6–1.0 cm

Tumor >1 cm

pN0

pN1mi Adjuvant endocrine therapy^dd,ee orAdjuvant chemotherapy^ff,ggwith

trastuzumab^hh and endocrine therapy^dd,ee See Follow-Up (BINV-16) Consider adjuvant endocrine therapy^dd,ee

± adjuvant chemotherapy^ff,ggwith trastuzumab^hh,ii(category 2B)

Adjuvant chemotherapy^ff,gg with trastuzumab^hh (category 1) and endocrine therapy^dd,ee,jj orAdjuvant chemotherapy^ff,gg with trastuzumab^hh + pertuzumab and endocrine therapy^dd,ee,jj

v See Special Considerations for Breast Cancer in Men (BINV-J).

y According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.

cc Although patients with cancers with 1%–100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with ER-low–positive (1%–10%) results. The ER-low–positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers. This should be considered in decision-making for other adjuvant therapy and overall treatment pathway. See Principles of Biomarker Testing (BINV-A).

dd Consider adjuvant bisphosphonate therapy in postmenopausal (natural or induced) patients receiving adjuvant therapy.

ee Evidence supports that the magnitude of benefit from surgical or radiation ovarian ablation in premenopausal women with hormone receptor-positive breast cancer is similar to that achieved with CMF alone. See Adjuvant Endocrine Therapy (BINV-K).

ff Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. Available data suggest that sequential or concurrent endocrine therapy with RT is acceptable.

See Adjuvant Endocrine Therapy (BINV-K) and Preoperative/Adjuvant Therapy Regimens (BINV-L).

Adjuvant chemotherapy^ff,gg

with trastuzumab (category 1) and endocrine therapy^dd,ee

gg There are limited data to make chemotherapy recommendations for those >70 y of age. See NCCN Clinical Practice Guidelines for Older Adult Oncology.

hh The prognosis of patients with T1a and T1b tumors that are node negative is uncertain even when HER2 is amplified or overexpressed. This is a population of breast cancer patients that was not studied in the available randomized trials. The decision for use of trastuzumab therapy in this cohort of patients must balance the known toxicities of trastuzumab, such as cardiac toxicity, and the uncertain, absolute benefits that may exist with trastuzumab therapy.

ii Adjuvant chemotherapy with weekly paclitaxel and trastuzumab (Tolaney et al. NEJM 2015) can be considered for T1,N0,M0, HER2-positive cancers, particularly if the primary cancer is hormone receptor-negative. The absolute benefit of HER2-based systemic chemotherapy is likely negligible in patients with hormone receptor-positive cancers and tumor size bordering on T1mic (<1 mm), when the estimated recurrence risk is less than 5% and endocrine therapy remains a viable option for systemic treatment.

jj Consider extended adjuvant neratinib following adjuvant trastuzumab- containing therapy for patients with HR-positive, HER2-positive disease with a perceived high risk of recurrence. The benefit or toxicities associated with extended neratinib in patients who have received pertuzumab is unknown.

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cc Although patients with cancers with 1%–100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data in the subgroup of cancers with ER-low–positive (1%–

10%) results. The ER-low–positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers. This should be considered in decision-making for other adjuvant therapy and overall treatment pathway. See Principles of Biomarker Testing (BINV-A).

SYSTEMIC ADJUVANT TREATMENT: NODE-NEGATIVE - HORMONE RECEPTOR-POSITIVE - HER2-NEGATIVE DISEASE^d,v,cc

pT1, pT2, or pT3;

and pN0

Tumor >0.5 cm

pN0 Consider adjuvant endocrine therapy^dd,ee (category 2B)

Strongly

consider 21-gene RT-PCR assay (category 1)^kk,ll

Not done

Recurrence score <26^mm Recurrence score 26–30

Recurrence score ≥31

Adjuvant endocrine therapy^dd,ee,mm

Adjuvant chemotherapy^ff,gg

followed by endocrine therapy^dd,ee Tumor ≤0.5 cm

Adjuvant endocrine therapy^dd,ee orAdjuvant chemotherapy^ff,gg followed by endocrine therapy^dd,ee(category 1)

Adjuvant endocrine therapy^dd,ee orAdjuvant chemotherapy^ff,gg

followed by endocrine therapy^dd,ee

• Lobular

• Mixed

See Follow-Up (BINV-16)

ff Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. Available data suggest that sequential or concurrent endocrine therapy with RT is acceptable. See Adjuvant Endocrine Therapy (BINV-K) and Preoperative/Adjuvant Therapy Regimens (BINV-L).

kk Other prognostic gene expression assays may be considered to help assess risk of recurrence but have not been validated to predict response to chemotherapy.

See Gene Expression Assays for Consideration of Addition of Adjuvant Systemic Chemotherapy to Adjuvant Endocrine Therapy (BINV-N).

ll Patients with T1b tumors with low-grade histology and no lymphovascular invasion should be treated with endocrine monotherapy as the TAILORx trial did not include patients with such tumors.

mm In women 50 years of age or younger with a recurrence score of 16–25, an exploratory analysis from the TAILORx study demonstrated a potential benefit to chemotherapy in younger patients. See Discussion.

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SYSTEMIC ADJUVANT TREATMENT: NODE-POSITIVE - HORMONE RECEPTOR-POSITIVE - HER2-NEGATIVE DISEASE^d,v,cc

pN1mi (≤2 mm axillary node metastasis) or N1ⁿⁿ (less than 4 nodes)

Node positive (4 or more

ipsilateral metastases >2 mm)^oo

Patient not a candidate for chemotherapy

Patient is a candidate for chemotherapy:

• Consider gene expression assay to assess

prognosis^pp and determine chemotherapy benefit Patient is a candidate for chemotherapy and gene expression assay not available:

• Use clinical and pathologic features for decision-making

Adjuvant endocrine therapy^dd,ee

orAdjuvant chemotherapy^ff,gg followed by endocrine therapy^dd,ee(category 1)

Adjuvant chemotherapy^ff,gg followed by endocrine therapy^dd,ee(category 1)

BINV-7 Initial decision-making

for adjuvant systemic chemotherapy based on:

• Clinical characteristics

• Tumor stage

• Pathology See

Follow-Up (BINV-16)

• Lobular

• Mixed

nn In N1mi and N1, gene expression assays are prognostic and not proven to be predictive of chemotherapy benefit but can be used to identify a low-risk population that when treated with proper endocrine therapy may derive little absolute benefit from chemotherapy. Regarding the 21-gene RT-PCR assay, a secondary analysis of a prospective trial suggests that the test is predictive for women with 1–3 involved ipsilateral axillary lymph nodes. Other gene expression assays have not proven to be predictive of chemotherapy benefit.

oo There are few data regarding the role of gene expression assays in women with four or more ipsilateral axillary lymph nodes. Decisions to administer adjuvant chemotherapy for this group should be based on clinical factors.

pp See Gene Expression Assays for Consideration of Addition of Adjuvant Systemic Chemotherapy to Adjuvant Endocrine Therapy (BINV-N).

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NCCN Guidelines Version 5.2020 Invasive Breast Cancer

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NCCN Guidelines Index Table of Contents Discussion SYSTEMIC ADJUVANT TREATMENT: HORMONE RECEPTOR-NEGATIVE - HER2-POSITIVE DISEASE^d,v,cc

• Lobular

• Mixed

pT1, pT2, or pT3; and pN0 or pN1mi (≤2 mm axillary node metastasis)

Tumor 0.6–1.0 cm

Tumor >1 cm

pN0

pN1mi

Consider adjuvant chemotherapy^gg,qq with trastuzumab^dd,hh,ii(category 2B) Consider adjuvant chemotherapy^gg,qq with trastuzumab^dd,hh,ii

Consider adjuvant chemotherapy^gg,qq with trastuzumab^dd,hh,ii

Adjuvant chemotherapy^gg,qq with trastuzumab^dd(category 1)

SeeFollow-Up (BINV-16) Tumor ≤0.5 cm

Adjuvant chemotherapy^gg,qq with trastuzumab^dd (category 1)

orAdjuvant chemotherapy^gg,qq with trastuzumab^dd + pertuzumab

hh The prognosis of patients with T1a and T1b tumors that are node negative is uncertain even when HER2 is amplified or overexpressed. This is a population of breast cancer patients that was not studied in the available randomized trials. The decision for use of trastuzumab therapy in this cohort of patients must balance the known toxicities of trastuzumab, such as cardiac toxicity, and the uncertain, absolute benefits that may exist with trastuzumab therapy.

ii Adjuvant chemotherapy with weekly paclitaxel and trastuzumab (Tolaney et al. NEJM 2015) can be considered for T1,N0,M0, HER2-positive cancers, particularly if the primary cancer is hormone receptor-negative. The absolute benefit of HER2-based systemic chemotherapy is likely negligible in patients with hormone receptor-positive cancers and tumor size bordering on T1mic (<1 mm), when the estimated recurrence risk is less than 5% and endocrine therapy remains a viable option for systemic treatment.

qq See Preoperative/Adjuvant Therapy Regimens (BINV-L).

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BINV-9 SYSTEMIC ADJUVANT TREATMENT: HORMONE RECEPTOR-NEGATIVE - HER2-NEGATIVE DISEASE^d,v,cc

• Lobular

• Mixed

• Metaplastic^z

pT1, pT2, or pT3; and pN0 or pN1mi (≤2 mm axillary node metastasis)

Tumor 0.6–1.0 cm

Tumor >1 cm

pN0 pN1mi

No adjuvant therapy^rr

Consider adjuvant chemotherapy^dd,gg,qq

Adjuvant chemotherapy^dd,gg,qq (category 1)

SeeFollow-Up (BINV-16) Tumor ≤0.5 cm

z There are rare subtypes of metaplastic carcinoma (eg, low-grade adenosquamous and low-grade fibromatosis-like carcinoma) that are considered to have a favorable prognosis without adjuvant systemic therapies.

cc Although patients with cancers with 1%–100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with ER- low–positive (1%–10%) results. The ER-low–positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers. This should be considered in decision-making for other adjuvant therapy and overall treatment pathway. See Principles of Biomarker Testing (BINV-A).

Consider adjuvant chemotherapy^dd,gg,qq

Adjuvant chemotherapy^dd,gg,qq (category 1)

gg There are limited data to make chemotherapy

recommendations for those >70 y of age. See NCCN Clinical Practice Guidelines for Older Adult Oncology.

rr In select patients with high-risk features (eg, very young women with high-grade histology), adjuvant chemotherapy may be considered (category 2B). See (BINV-L).

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NCCN Guidelines Version 5.2020 Invasive Breast Cancer

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NCCN Guidelines Index Table of Contents Discussion SYSTEMIC ADJUVANT TREATMENT: FAVORABLE HISTOLOGIES^v,aa

z There are rare subtypes of metaplastic carcinoma (eg, low-grade

adenosquamous and low-grade fibromatosis-like carcinoma) that are considered to have a favorable prognosis without adjuvant systemic therapies.

aa To be associated with favorable prognosis, the favorable histologic type should be pure (>90% as classified on the surgical excision, not core biopsy alone), not high grade, and HER2 negative. If non-typical pathologic or clinical features are present, consider treating as ductal/NST.

bb Correlation of histology, hormone receptor, and HER2 status should always be done with awareness of unusual/discordant or borderline results. See Principles of Biomarker Testing (BINV-A).

ff Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. Available data suggest that sequential or concurrent endocrine therapy with RT is acceptable.

See Adjuvant Endocrine Therapy (BINV-K) and Preoperative/Adjuvant Therapy Regimens (BINV-L).

gg T here are limited data to make chemotherapy recommendations for those >70 y of age. See NCCN Clinical Practice Guidelines for Older Adult Oncology.

ss Encapsulated papillary carcinoma (EPC) without associated conventional invasion is staged as pTis because behavior is similar to DCIS (per AJCC). Solid papillary carcinoma (SPC) should be specified as in situ or invasive based on WHO criteria but both forms have favorable outcomes.

• Adenoid cystic carcinoma

• Salivary secretory carcinoma

• Other rare types^z

• Pure tubular

• Pure mucinous

• Pure cribriform

• Encapsulated or solid papillary carcinoma^ss

ER-positive and/or PR-positive, HER2-negative^bb

ER-negative andPR-negative, HER2-negative^bb

pT1, pT2, or pT3;

and pN0 or pN1mi (≤2 mm axillary node metastasis)

<1 cm 1–2.9 cm

≥3 cm

Consider adjuvant endocrine therapy^dd for risk reduction Consider adjuvant endocrine therapy^dd,ee

Adjuvant endocrine therapy^dd,ee

Adjuvant endocrine therapy^dd,ee ± adjuvant chemotherapy^ff,gg

SeeFollow-Up (BINV-16)

Limited available data support local therapy only with consideration for systemic/targeted therapies only in node-positive disease

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CLINICAL

STAGE WORKUP^a

≥T2,M0 or ≥N1,M0^tt

(if considering preoperative systemic therapy)

WORKUP PRIOR TO PREOPERATIVE SYSTEMIC THERAPY

BINV-11

• History and physical exam

• Diagnostic bilateral mammogram; ultrasound as necessary

• Axillary assessment with exam consider ultrasound

percutaneous biopsy of suspicious nodes^uu

• Pathology review^c

• Determination of tumor ER/PR status and HER2 status^d

• Genetic counseling if patient is at risk^e for hereditary breast cancer

• Counseling for fertility concerns if premenopausal; pregnancy test in all women of childbearing potential^f (If pregnant, see PREG-1)

• Assess for distress^g

Additional studies consider:^h

• CBC

• Comprehensive metabolic panel, including liver function tests and alkaline phosphatase

• Chest diagnostic CT with contrast

• Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast

• Bone scan or sodium fluoride PET/CTⁱ (category 2B)

• FDG PET/CT^j.k (optional)

• Breast MRI^b (optional), with special consideration for mammographically occult tumors

For operable breast cancers: See Breast and Axillary Evaluation Prior to Preoperative Systemic Therapy (BINV-12)

For inoperable breast cancers: See Preoperative Systemic Therapy (BINV-14)

b Breast MRI may be useful for characterizing axillary and/or internal mammary nodal disease. See Principles of Dedicated Breast MRI Testing (BINV-B).

c The panel endorses the College of American Pathologists Protocol for pathology reporting for all invasive and noninvasive carcinomas of the breast.

http://www.cap.org.

e For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic.

f See Fertility and Birth Control (BINV-C).

g See NCCN Guidelines for Distress Management.

h Routine systemic staging is not indicated for early breast cancer in the absence of symptoms.

i Bone scan or sodium fluoride PET/CT may not be needed if FDG PET/CT is performed and clearly indicates bone metastasis, on both the PET and CT component.

j FDG PET/CT can be performed at the same time as diagnostic CT. The use of PET or PET/CT is not indicated in the staging of clinical stage I, II, or operable stage III breast cancer. FDG PET/CT is most helpful in situations where standard staging studies are equivocal or suspicious, especially in the setting of locally advanced or metastatic disease.

k FDG PET/CT may also be helpful in identifying unsuspected regional nodal disease and/or distant metastases in locally advanced breast cancer when used in addition to standard staging studies.

tt See Principles of Preoperative Systemic Therapy (BINV-M).

uu At the time of axillary node sampling, a clip or tattoo should be placed to permit verification that the biopsy-positive lymph node has been removed at the time of definitive surgery.

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NCCN Guidelines Version 5.2020 Invasive Breast Cancer

^TM

Prior to preoperative systemic therapy, perform:^vv

• Core biopsy of breast with placement of image- detectable marker(s), if not previously performed, must be done to demarcate the tumor bed for surgical management after preoperative systemic therapy

• Axillary imaging with ultrasound or MRI (if not previously done)

• Biopsy of suspicious and/or clinically positive axillary and lymph nodes, if not previously done

See Surgical Treatment and Adjuvant Therapy After Preoperative Systemic Therapy (BINV-13)

Preoperative systemic therapy based on hormone receptor (HR) and HER2 status^qq,tt

vv Sentinel node biopsy can be considered prior to preoperative systemic therapy if the determination of nodal status will influence surgical and/or systemic therapy choices.

OPERABLE DISEASE: BREAST AND AXILLARY EVALUATION PRIOR TO PREOPERATIVE SYSTEMIC THERAPY

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BINV-13

ww The accurate assessment of in-breast tumor or regional lymph node response to preoperative systemic therapy is difficult, and should include physical examination and performance of imaging studies (mammogram and/or breast ultrasound and/or breast MRI) that were abnormal at the time of initial tumor staging. Selection of imaging methods prior to surgery should be determined by the multidisciplinary team.

xx Complete planned chemotherapy regimen course if not completed preoperatively.

OPERABLE DISEASE:

SURGICAL TREATMENT AND ADJUVANT THERAPY AFTER PREOPERATIVE SYSTEMIC TREATMENT

Partial response,

lumpectomy not possible orConfirmed progressive disease at any time, lumpectomy not possible Complete response orPartial response, lumpectomy possible

Mastectomy and surgical axillary staging^l (see BINV-D) + reconstruction (optional)^p

Lumpectomy with surgical axillary staging^l(see BINV-D)

SURGICAL TREATMENT ADJUVANT THERAPY

RESPONSE^ww

Adjuvant systemic therapy^tt,xx (see BINV-15) andPost-lumpectomy adjuvant RT^r

• Clinical N1 and ypN0: Adjuvant RT to the whole breast with or without boost to the tumor bed; and strongly consider radiation to the supraclavicular/infraclavicular region, area, internal mammary nodes, and any part of the axillary bed at risk

• Any ypN+: Adjuvant RT to the whole breast (with or without boost to the tumor bed) with inclusion of the supraclavicular/

infraclavicular region, area, internal mammary nodes, and any part of the axillary bed

Adjuvant systemic therapy^tt,xx (see BINV-15) andPost-mastectomy adjuvant RT^r

• Clinical N1 and ypN0: Strongly consider RT to the chest wall, supraclavicular/infraclavicular regions, internal mammary nodes, and any part of the axillary bed at risk

• Any ypN+: RT is indicated to the chest wall + supraclavicular/

infraclavicular regions, internal mammary nodes, and any part of the axillary bed at risk

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NCCN Guidelines Version 5.2020 Invasive Breast Cancer

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ww The accurate assessment of in-breast tumor or regional lymph node response to preoperative systemic therapy is difficult, and should include physical examination and performance of imaging studies (mammogram and/or breast ultrasound and/or breast MRI) that were abnormal at the time of initial tumor staging. Selection of imaging methods prior to surgery should be determined by the multidisciplinary team.

xx Complete planned chemotherapy regimen course if not completed preoperatively.

yy For patients with skin and/or chest wall involvement (T4 non-inflammatory) prior to preoperative systemic therapy, breast conservation may be performed in carefully selected patients based on a multidisciplinary assessment of local recurrence risk. In addition to standard contraindications to breast conservation (see BINV-G), exclusion criteria for breast conservation include: inflammatory (T4d) disease before preoperative systemic therapy and incomplete resolution of skin involvement after preoperative systemic therapy.

LOCOREGIONAL TREATMENT Response to

preoperative

systemic therapy^ww and tumor is operable

Consider additional systemic chemotherapy and/or

preoperative radiation^r

Individualize treatment INOPERABLE OR LOCALLY ADVANCED DISEASE (NON-INFLAMMATORY):

PREOPERATIVE SYSTEMIC THERAPY AND SUBSEQUENT TREATMENT

Mastectomy and surgical axillary staging^l

+ reconstruction (optional)^p orLumpectomy with surgical axillary staging^l,yy

RESPONSE^ww

Preoperative systemic therapy^tt

Adjuvant systemic therapy^xx (see BINV-15) and Adjuvant RT^r to the whole breast or chest wall, supraclavicular/infraclavicular regions, internal mammary nodes, and any part of the axillary bed at risk

No response to

preoperative systemic therapy^wwand tumor remains inoperable

Response to preoperative

systemic therapy^ww and tumor is operable

No response to

preoperative systemic therapy^wwand tumor is inoperable

Follow pathway above

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BINV-15

zz If HER2-